Integrated Genomic Approaches to Elucidate the Genetic Basis of Brugada Syndrome in Taiwanese Patients

Q: What is the clinical evidence from this study?

Study design: Case-Control. Population: Brugada Syndrome (n=1530). Intervention: ZNF451 locus (rs76107757) vs. Healthy controls. Primary outcome: Genetic association with Brugada Syndrome (OR 9.845, p=6.853e-11).

Chayanika Goswami; Jyh‐Ming Jimmy Juang; Tzu‐Pin Lu; Jinn‐Moon Yang; Amrita Chattopadhyay; Eric Y. Chuang

doi:10.1177/11779322251385926

October 1, 2025Bioinformatics and Biology InsightsOpen Access

Integrated Genomic Approaches to Elucidate the Genetic Basis of Brugada Syndrome in Taiwanese Patients

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Key result

Novel ZNF451 locus linked to ~10-fold greater Brugada syndrome risk in Taiwanese patients.

OR 9.845
P 6.853e-11
n=1,530

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Why the study?

Brugada syndrome is a rare cardiac arrhythmia with a complex and largely unexplained genetic basis.

Key Points

To identify genetic susceptibility loci and elucidate the complex genomic architecture of Brugada syndrome in Taiwanese patients.
Analyzed genomic data from 214 Taiwanese Brugada syndrome cases and 1,316 controls using a population-specific imputation panel.
Applied genome-wide association study (GWAS), copy number variation (CNV) analysis, and rare-variant association test (RVAT) approaches.
GWAS revealed four genome-wide significant SNPs across SCN10A, ZNF451, and RP11-510I5, with the ZNF451 locus demonstrating a strong association (OR = 9.845, P = 6.8e-11).
Total SNP-heritability was 0.18 (SE = 0.20), with the three primary risk loci accounting for 0.13 (SE = 0.02) of the phenotypic variance.
RVAT identified the non-coding RNA gene ZNF451-AS1, while CNV analysis detected case-enriched structural variants, including a duplication involving HRAS.

Study Design

Type

Case-Control (n=1,530)

Structured PICO

P

Population

214 Taiwanese patients with Brugada syndrome (BrS) and 1316 healthy controls (after quality control). Cases had a mean age of 40.8 years, 86.4% male, with 69.6% showing spontaneous type 1 Brugada ECG pattern.

O

Outcome

Identification of genetic susceptibility loci for Brugada syndrome using genome-wide association study (GWAS), copy number variation (CNV) analysis, and rare-variant association test (RVAT)surrogate

Main Result

Effect estimate: OR 9.845

Absolute Event Rate: 0.0864% vs 0.0098%

p-value: p=6.853e-11

This study identifies ZNF451 as a novel, highly significant susceptibility locus for Brugada syndrome in Taiwanese patients, highlighting the importance of population-specific genomic resources.

Limitations

Lack of replication in an independent cohort
Modest sample size of the Merged-TWN-panel may have reduced power to detect very rare variants
Exploratory case-case Fisher's exact test showed no significant variants
eQTL analysis did not yield significant findings likely due to underrepresentation of Asian ancestry populations in transcriptomic resources

Implication

May inform ancestry-specific Brugada risk assessment; extends GWAS evidence but leaves open clinical utility.

Abstract

Brugada syndrome (BrS) is a rare cardiac arrhythmia with a complex and largely unexplained genetic basis. In this study, we analysed genomic data from 214 Taiwanese BrS cases and 1316 controls to uncover susceptibility loci using genome-wide association study (GWAS), copy number variation (CNV) analysis, and rare-variant association test (RVAT). Imputation with a population-specific Merged-TWN-panel yielded the highest accuracy across SNP categories. GWAS identified four genome-wide significant SNPs across three loci, including SCN10A , ZNF451 , and RP11-510I5 , with the ZNF451 locus showing a strong association (OR = 9.845, P = 6.8e-11). The total SNP-heritability for BrS was estimated at 0.18 ( SE = 0.20), and SNPs located in the 3 risk loci regions accounted for 0.13 ( SE = 0.02) of the phenotypic variance. Functional annotation revealed several regulatory non-coding SNPs, and gene-based analysis confirmed SCN10A as significant. Notably, ZNF451-AS1 , a non-coding RNA gene overlapping the ZNF451 region, was identified via RVAT, suggesting that both common and rare variants at this locus contribute to BrS risk. CNV analysis further identified potential case-enriched regions, including a duplication involving HRAS . These findings underscore the importance of population-specific genomic resources and highlight ZNF451 as a key susceptibility locus, bridging both common and rare-variant contributions to BrS.

Discussion

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Cite This Study

Goswami et al. (2025) conducted a case-control in Brugada Syndrome (n=1,530). ZNF451 locus (rs76107757) vs. Healthy controls was evaluated on Genetic association with Brugada Syndrome (OR 9.845, p=6.853e-11). Genome-wide association analysis identified a novel susceptibility locus at ZNF451 (rs76107757) strongly associated with Brugada syndrome risk (OR 9.845, P = 6.8e-11) in Taiwanese patients.

synapsesocial.com/papers/6a0e5993a0467873efc84064 https://doi.org/10.1177/11779322251385926

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Integrated Genomic Approaches to Elucidate the Genetic Basis of Brugada Syndrome in Taiwanese Patients

Figures

Key Points

Study Design

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

Integrated Genomic Approaches to Elucidate the Genetic Basis of Brugada Syndrome in Taiwanese Patients

Figures

Key Points

Study Design

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

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